The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

Riebeling, Christian; Pirow, Ralph; Becker, Klaus M.; Buesen, Roland; Eikel, Daniel; Kaltenhäuser, Johanna; Meyer, Frauke; Nau, Heinz; Slawik, B.; Visan, A.; Volland, Jutta; Spielmann, Horst; Luch, Andreas; Seiler, A.

doi:10.1093/toxsci/kfr001

Cited by 29 publications

(9 citation statements)

References 48 publications

(90 reference statements)

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“…The embryotoxic/teratogenic properties of Valproic acid (2-propylvaleric acid) have been studied in several animal model systems (zebrafish, Xenopus , chicken, mouse, rat, hamster, gerbil, rabbit, dog and rhesus monkey) in vivo and in vitro (mouse ES cells) for over 40 years [Gurvich et al, 2005; Hsieh et al, 2012; Nau and Hendrickx, 1987; Riebeling et al, 2011]. When administered in sufficiently high doses (e.g., 200-800 mg/kg/day in a mouse or rat) to pregnant dams, depending on the route (orally, subcutaneously, intraperitoneally or intravenously), gestational stage, species and strain, VPA invariably produces a range of developmental defects that increase in a dose-dependent manner.…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic drugs and pregnancy outcomes

Wlodarczyk

Palacios

George

et al. 2012

American J of Med Genetics Pt A

112

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The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos.

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Section: Antiepileptic Drugsmentioning

confidence: 99%

Antiepileptic drugs and pregnancy outcomes

Wlodarczyk

Palacios

George

et al. 2012

American J of Med Genetics Pt A

112

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“…Potency ranking of available in vivo data correlated well with potency ranking in the EST (21). Other groups studied VPA and six analogs using the original prediction model and the ReProGlo model, obtaining comparable results (20,22).…”

Section: The Applicability Domain Of Compound Classes For the Estmentioning

confidence: 67%

“…A second chemical class evaluated was valproic acid (VPA) and its analogs (20)(21)(22). In one study, VPA and five analogs with different potency were tested as a chemical class in the EST.…”

Section: The Applicability Domain Of Compound Classes For the Estmentioning

confidence: 99%

Innovative approaches in the embryonic stem cell test (EST)

Theunissen

Piersma²

2012

Front Biosci

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The embryonic stem cell test (EST) is a high-throughput in vitro screening assay for developmental toxicity free of animal use. The EST uses the ability of murine embryonic stem cells to differentiate into the mesodermal cardiac lineage in combination with two cytotoxicity test systems. Validation of the EST showed that the test system is very promising as an alternative method to animal testing, however to optimize predictability and increase knowledge on the applicability domain of the EST, improvements to the method were proposed and studied. In this review we discuss the first definition of the EST followed by the innovative approaches which have been proposed to increase the predictivity of the EST, including implementation of molecular endpoints in the EST, such as omics technologies and the addition of alternative differentiation models to the testing paradigm, such as neural and osteoblast differentiation and the use of human stem cells. These efforts to improve the EST increase the value of embryonic stem cells used as in vitro systems to predict developmental toxicity.

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“…(3). IC50 was detected around 1 x 10 -4 M, indicating a specific toxic effect, since IC50 cytotoxicity reported in literature for 3T3 cells is on average 2.8 mM [29].…”

Section: Cytotoxicitymentioning

confidence: 70%

Characterisation of a Neural Teratogenicity Assay Based on Human ESCs Differentiation Following Exposure to Valproic Acid

Colleoni

Galli²,

Gaspar³

et al. 2012

Current Medicinal Chemistry

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The development of in vitro testing strategies for chemical and drug screening is a priority need in order to protect human health, to increase safety, to reduce the number of animals required for conventional testing methods and finally to meet the deadlines of current legislations. The aim of this work was to design an alternative testing method based on human embryonic stem cells for the detection of prenatal neural toxicity. For this purpose we have created a model based on the generation of neural rosettes, reproducing in vitro the gastrulation events recapitulating the formation of the neural tube in vivo. To validate the model we have exposed this complex cell system to increasing concentrations of valproic acid, a known teratogenic agent, to analyse the morphological and molecular changes induced by the toxicant. Specific assays were applied to discriminate between cytotoxicity and specific neural toxicity. Transcriptomic analysis was performed with a microarray Affimetrix platform and validated by quantitative real time RT-PCR for the expression of genes involved in early neural development, neural tube formation and neural cells migration, key biological processes in which the effect of valproic acid is most relevant. The results demonstrated that neural rosette cells respond to valproic acid exposure with molecular and morphological changes similar to those observed in vivo, indicating that this method represents a promising alternative test for the detection of human prenatal neural toxicity.

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The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

Cited by 29 publications

References 48 publications

Antiepileptic drugs and pregnancy outcomes

Antiepileptic drugs and pregnancy outcomes

Innovative approaches in the embryonic stem cell test (EST)

Characterisation of a Neural Teratogenicity Assay Based on Human ESCs Differentiation Following Exposure to Valproic Acid

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